Integrin-Mediated Regulation of TGF-Beta Signaling and Tumorigenesis

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DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death in women in the United States. Invasion and metastasis are the most lethal characteristics of breast cancer and the leading cause of breast cancer-related death. TGF-? normally inhibits breast cancer development by preventing mammary epithelial cell (MEC) proliferation, or by inducing MEC apoptosis. Mammary tumorigenesis counteracts the tumor suppressing activities of TGF-?, thus enabling TGF-? to stimulate breast cancer invasion and metastasis. Fundamental gaps exist in our knowledge of how malignant MECs overcome the cytostatic actions of TGF-?, and of how TGF-? stimulates the development and progression of mammary tumors. These knowledge gaps have prevented science and medicine from developing treatments effective in antagonizing the oncogenic activities of TGF-? in developing and progressing breast cancers. We recently established ?v?3 integrin and Src as essential mediators of TGF-?-stimulated MAP kinase activation, cell invasion, and epithelial-to-mesenchymal transition (EMT) in normal and malignant MECs. Based on these and other preliminary findings, we hypothesize that aberrant activation of ?v?3 integrin and Src in developing breast cancers promotes the oncogenic function of TGF-? and its induction of breast cancer cell EMT, invasion, and metastasis by (i) inducing formation of ?v?3 integrin:TGF-? receptor complexes; (ii) stimulating Tyr phosphorylation of the TGF-¿ type I (T¿R-I) and type II (T¿R-II) receptors; and (iii) coordinating the formation Shc:Grb2:Gab1/2 complexes that amplify activation of MAP kinases by TGF-¿. A corollary states that inactivating av¿3 integrin and Src function will prevent the conversion of TGF-¿ from a suppressor to a promoter of breast cancer growth and invasion, thereby alleviating breast cancer development and progression stimulated by TGF-¿. Theses hypotheses will be addressed by three specific aims. Specific Aim 1 will identify the ¿3 integrin and T¿R-II determinants that mediate av¿3 integrin:T¿R-II complex formation and mutants lacking these functions will be used to establish the role of av¿3 integrin:T¿R-II complexes in mediating oncogenic signaling by TGF-¿ in normal and malignant MECs. Specific Aim 2 will identify the Tyr residues in T¿R-I and T¿R-II that are phosphorylated by Src and mutants lacking these functions will be used to determine the impact of these reactions on TGF-¿ function in normal and malignant MECs. Specific Aim 3 will determine the effectiveness of interdicting av¿3 integrin and Src function in preventing TGF-¿ stimulation of breast cancer cell growth, invasion, angiogenesis, and metastasis in mice. These studies will provide valuable information on how TGF-¿ promotes breast cancer invasion and metastasis, and more importantly, on how to control these deadly processes by targeting the oncogenic activities of TGF-¿ through the development and use of av¿3 integrin and Src antagonists. Moreover, application of our findings will enable science and medicine to, one day, improve the prognosis and treatment of patients with metastatic breast cancer.